There are an estimated 1.6-3.8 million sports-related concussions each year. Human concussions do not usually cause macroscopic lesions visible by CT or MRI, but multiple concussions can lead to axonal injury, long-term cognitive impairments, and neurological disease. These long- term changes are best described in professional athletes, termed dementia pugilistica in boxers and chronic traumatic encephalopathy in other athletes. Studies in these individuals have shown that activation of the brain's resident immune cells, microglia, occurs after traumatic brain injury in areas of axonal injury. Microglial activation in white matter has also been noted after concussion in post- mortem-samples. Whether this response contributes to ongoing axonal injury, protects against further damage, or is neutral in concussion is not known. To fill this knowledge gap, our lab has developed a reproducible model of repetitive concussive injury in mouse similar to Longhi and colleagues (Neurosurgery 2005). In this model, two closed-skull impacts delivered 24 hours apart result in a consistent pattern of axon degeneration and microglial activation without neuronal cell loss. The central hypothesis of this proposal is that persistent microglial activatio following repetitive concussive injury in mouse results in axon degeneration and electrophysiological compromise. To address this hypothesis, the phenotype of microglia within white matter will be compared across time points. A microglial-specific toxin will be administered to determine how elimination of microglia effects axonal degeneration in both the acute and chronic injury phase. If successful, these experiments will greatly increase our knowledge of the role of activated microglia in axonal injury in this mouse model of repetitive concussive trauma. These results may deepen our understanding of the pathological processes that cause cognitive impairments in concussed individuals and could have important implications for therapeutics. For these experiments the applicant will be trained in multiple techniques including small animal surgery, immunohistochemistry, stereology, flow cytometry, qPCR, extracellular brain slice electrophysiology, and statistical analysis of quantitative data. PUBLIC HEALTH RELEVANCE: There are an estimated 1.6-3.8 million sports-related concussions each year and mounting evidence that multiple concussions result in long-term cognitive impairments and increased risk for Alzheimer's disease. After brain injury microglia, the immune cells of the brain, invade injured regions and may produce toxic compounds that result in tissue damage. This proposal is aimed at determining how microglia contribute to concussive injury, which could ultimately lead to therapeutics that reduce lasting impairments in concussed individuals.